This invention is in the area of organic synthesis and is in particular a method for synthesis of high molecular weight polyanhydrides.
Synthesis of aromatic polyanhydrides was first reported in 1909. In the 1930's, Carothers and Hill prepared a series of aliphatic polyanhydrides intended as substitutes for polyesters in textile applications, as reported in J. Am. Chem. Soc., 52, 4110 (1930), and J. Am. Chem. Soc., 54, 1569 (1932). In the late 1950's, A. Conix reported poly[bis(p-carboxyphenoxy)alkane anhydrides] having a much improved hydrolytic resistance as well as excellent film and fiber-forming properties, in Makromol. Chem., 24, 76 (1957), and J. Polym. Sci., 29, 343 (1958). These polymers are insoluble in common organic solvent, however, so they cannot be solvent cast. Subsequent studies examined a number of aromatic and heterocyclic polyanhydrides. Including coploymers, over one hundred polyanhydrides had been prepared by 1965. However, these polyanhydrides were never commercialized, presumably due to the problem of hydrolytic instability.
High molecular weight polyanhydrides are essential for biomedical applications where superior physico-mechanical properties including film forming, high tensile strength, yield of break and impact are required. Although synthesis of polyanhydrides is well documented, polyanhydrides having a molecular weight average in excess of 15,000 to 20,000 and an intrinsic viscosity in organic solvents of greater than 0.3 dl/g are not synthesized using any of the known methods. Previous reports of polyanhydrides having higher molecular weights were based on estimated molecular weights. Controlled studies using instrumentation not available when these reports were made have shown that the polyanhydrides produced by solution polymerization and melt polymerization have a molecular weight average of a few thousand up to at most 20,000. The low molecular weight polyanhydride polymers are limited by their low molecular weight (generally 12,500 mw) and corresponding low intrinsic viscosity in solution (approximately 0.1 to 0.3 dl/g in organic solvents at room temperature). Although polyanhydrides are useful in controlled release drug delivery systems due to their hydrolytic instability and the fact that they degrade into monomeric diacids which are highly biocompatible, as shown by tissue response and toxicological studies, the rate of degradation is too rapid for many applications.
Further, the manufacture of controlled release devices is limited since the devices incorporating the low molecular weight polyanhydrides can only be manufactured in two ways: by mixing the powdered polyanhydride with the bioactive substances and then pressing the mixture into devices or by melting the polyanhydrides and bioactive substances at a relatively high temperature. The first method frequently results in a non-homogeneous mixture or poor release kinetics and the second causes degradation of the incorporated drugs or a reaction between the drugs and the polyanhydrides.
It is desirable to be able to solvent cast the polyanhydrides to form films for the manufacture of biomedical devices. Increasing the aromatic content and/or the molecular weight of these polyanhydrides would impart film forming properties to the polymers. Films have a number of advantages including a more homogeneous distribution of bioactive material, the ability to be cast as a sheet at ambient temperature for cutting up into the desired sizes and shapes and desirable release kinetics for controlled release of bioactive materials.
In recent years, much research has been directed to developing polymeric compositions and delivery systems for the programmed release of biologically active agents, especially drugs, over preselected periods of time. The purpose of these programmed release systems is to dispense the biologically active substance at a controlled and, preferably, constant rate after in vivo implantation into a patient. One application of these systems is an improved therapeutic regimen wherein a pharmaceutically active drug is released in a beneficial and reliable manner with the minimum potential for complications or failure to provide adequate dosage.
Although controlled release of biologically active substances has been accomplished in several ways, the preferred mechanism is to utilize an implanted polymeric matrix which degrades in vivo into soluble degradation products. The distinct advantage of this method is the elimination of the need for surgical removal of the article at a later date. Despite the desirability of such a mechanism, however, the development of polymeric matrix systems using bioerodible polymers for controlled release of active agents has not progressed quickly. In fact, few bioerodible polymers have been developed for biomedical or in vivo use. Of these, a few polymeric formulations were designed specifically for the release of biologically active substances. Examples of useful polycarbonate and polyorthoester polymeric compositions are described in U.S. Pat. No. 4,070,347. Polylatic acid and polylatic/glycolic acid copolymers are commercially available substances used for controlled release at biologically active substances.
For a polymer to be useful as a matrix for controlled release of a biologically active substance, surface erosion of the polymer should be the determining factor for release of the entrapped substance. Further, to be suitable for use in vivo, the polymeric matrix composition must degrade into low molecular weight, non-toxic products. Ideally, the polymeric matrix erodes at a preselected, constant rate and the biologically active substance is released at a zero-order rate, without regard to the concentration of any other chemical component. To obtain a zero-order release reaction of active substances from the matrix, it is necessary to utilize a matrix geometry which does not change substantially in surface area as a function of time.
To be useful as a matrix for controlled release of a biologically active substance, the composition must also not undergo bulk erosion which often occurs in addition to, or in place of, surface erosion, rendering the entire polymer composition sponge-like and causing breakup of the matrix. To erode heterogeneously, the polymer should be hydrophobic yet contain water labile linkages. Bulk erosion is directly due to the hydrophilic nature of most bioerodible polymeric compositions. Hydrophilic bioerodible polymers incorporate water which is drawn into the center of the matrix. Polymers which undergo bulk erosion include polylactic acid, polyglutamic acid, polycaprolactone and lactic/glycolic acid copolymers.
One hydrophobic composition which is useful for delivery of biologically active substances is polyorthoesters. An advantage to their use is that hydrolysis of orthoester is pH sensitive and pH may therefore be used for regulation of the release of the active substance. However, all polyorthoesters synthesized to date are often too hydrolytically stable for use in controlled release systems without acid catalysts included within the matrix to promote bioerosion. As a consequence, the polyorthoester polymers-additive system swell substantially when attempts are made to suppress degradation in the interior of the matrix, the rate of swelling often dominating and affecting the rate of release for the active substance more than the rate of erosion itself.
As described in co-pending patent application Ser. No. 820,290, filed Jan. 21, 1986, entitled "Bioerodible polyanhydrides for Controlled Drug Delivery" by Robert S. Langer, Howard Rosen, Robert J. Lonhardt and Kam Leong, other compositions which are useful as hydrophobic polymeric matrices for the controlled release of biologically active substances after implantation are polyanhydride polymers prepared by a modification of the melt polycondensation synthesis method of Conix, described in Macro Synth. 2, 95-98 (1966), in which the prepolymer is recrystallized initially to provide a more pure, higher molecular weight unit for polymerization. Selected polyanhydrides completely degrade to their monomers under physiological conditions at rates useful for drug delivery. Degradation rates are high in polymers or copolymers of sebacic acid. Erosion rates are highly dependent on the number of methylene groups. As with the other reported polyanhydrides, these polymers also have low molecular weight (up to 15,000) and intrinsic viscosities (up to 0.3 dl/g). As a result, their physico-mechanical properties and release kinetics are less than is desired.
It is therefore an object of the invention to provide a method for synthesizing high molecular weight polyanhydride polymers.
It is another object of the invention to provide less hydrophobic high molecular weight polyanhydride polymers for use in biomedical applications, especially controlled release of biologically active substances in vivo.